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BDNF-mediated neurotransmission relies upon a myosin VI motor complex

Nature Neuroscience volume 9, pages 1009–1018 (2006)Cite this article

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Abstract

Brain-derived neurotrophic factor (BDNF) has been implicated in higher-order cognitive functions and in psychiatric disorders such as depression and schizophrenia. BDNF modulates synaptic transmission and plasticity primarily through the TrkB receptor, but the molecules involved in BDNF-mediated synaptic modulation are largely unknown. Myosin VI (Myo6) is a minus end–directed actin-based motor found in neurons that express Trk receptors. Here we report that Myo6 and a Myo6-binding protein, GIPC1, form a complex that can engage TrkB. Myo6 and GIPC1 were necessary for BDNF-TrkB–mediated facilitation of long-term potentiation in postnatal day 12–13 (P12–13) hippocampus. Moreover, BDNF-mediated enhancement of glutamate release from presynaptic terminals depended not only upon TrkB but also upon Myo6 and GIPC1. Similar defects in basal synaptic transmission as well as presynaptic properties were observed in Myo6 and GIPC1 mutant mice. Together, these results define an important role for the Myo6-GIPC1 motor complex in presynaptic function and in BDNF-TrkB–mediated synaptic plasticity.

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Figure 1: Trk associates with GIPC1-Myo6 motor complex.
Figure 2: Synaptic localization of GIPC1.
Figure 3: Impaired basal synaptic transmission in Myo6- and GIPC1-deficient mice.
Figure 4: Presynaptic deficits in Myo6- and GIPC1-deficient mice.
Figure 5: GIPC1 and Myo6 are necessary for BDNF-induced synaptic transmission.
Figure 6: TrkB cell surface expression and signaling.
Figure 7: Reduction in the number of neurotransmitter release sites in Myo6sv/sv and Gipc1−/− mice.
Figure 8: Requirement of GIPC1 and Myo6 for BDNF-induced glutamate release.

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Notes

  1. *NOTE: In the supplementary information initially published online to accompany this article, the units for values reported in the supplementary methods are incorrect. The correct unit should be µ. The error has been corrected online.

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Acknowledgements

We are grateful to N. Jenkins (National Cancer Institute, Frederick, Maryland) for porcine Myo6 cDNAs; T. Hasson (University of California, San Diego) for anti-Myo6 antibody; I. Taniuchi and D. Littman (New York University) for advice on the generation of Gipc1 mutant mice; A. Auerbach and staff members of the Transgenic Animal Facility (New York University) for assistance; R. Rajagopal, J.C. Arevalo, M. Beyna, D.B. Pereira and A.H. Kim for reagents and advice; D.C. Powell for writing the program for Matlab analysis; and I. Orozco and P.K. Hsu (Columbia University, New York) for assistance during electrophysiological experiments. This work was funded by US National Institutes of Health grants to M.V.C. (HD23315 and NS21072), O.A. (NS40045) and T.M. (HL-18974 and DA08259).

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Authors and Affiliations

  1. Departments of Cell Biology, Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Physiology and Neuroscience, New York University School of Medicine, 540 First Avenue, New York, 10016, New York, USA

    Hiroko Yano & Moses V Chao

  2. Department of Pathology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 West 168th Street, New York, 10032, New York, USA

    Ipe Ninan, Hong Zhang & Ottavio Arancio

  3. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 411 East 69th Street, New York, 10021, New York, USA

    Teresa A Milner

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Contributions

H.Y. performed the cell and molecular biology experiments and the mouse genetics. T.A.M. conducted the electron microscopy experiments. O.A. supervised and I.N and H.Z. performed FM dye and electrophysiological studies.

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Correspondence to Moses V Chao.

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Supplementary information

Supplementary Fig. 1

Association of Trk with Myo6 through GIPC1. (PDF 846 kb)

Supplementary Fig. 2

Localization and movement of GIPC1-GFP punctae in live hippocampal processes. (PDF 1306 kb)

Supplementary Fig. 3

Normal synaptic fatigue and LTP in adult Myo6- and GIPC1-deficient mice. (PDF 923 kb)

Supplementary Methods (PDF 125 kb)

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Yano, H., Ninan, I., Zhang, H. et al. BDNF-mediated neurotransmission relies upon a myosin VI motor complex. Nat Neurosci 9, 1009–1018 (2006). https://doi.org/10.1038/nn1730

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